Cresset User Group Meeting 2018

The Cresset team and I would be delighted to welcome you to the Cresset User Group Meeting 2018, where we will be presenting our strongest ever scientific program.

In addition to invited presentations from leading researchers in our field, Cresset scientists will present our latest science and will showcase upcoming applications to help your chemistry teams design the best molecules as efficiently as possible.

Whether you are new to Cresset, have been with us from the beginning, or are just intrigued to find out more about the solutions we offer, I look forwards to seeing you there.

Who should attend by industry?

Feedback from previous meetings

“Very well organized, with a great talk line-up. Everyone is so friendly and approachable. The meeting is reminiscent of a Gordon conference. Looking forward to coming back next year.”

“The meeting was really great, I learnt quite a few new things, or deepened my knowledge of established applications. It was also a great opportunity for networking, talking to other users and to members of the Cresset team.”

“I really enjoyed attending the users group meeting, my first. It was great to see how the suite of software has evolved over many years to become a readily accessible, unique set of applications regularly used by practicing medicinal chemists. The whole team at Cresset should be proud of what they have achieved in pursuing and developing the original vision.”

“Selection of services topics were excellent and most informative. Gained a lot of new information and ideas.”

Exhibitors, June 21

Workshops

Workshops will run from 08:30hrs to 14:00hrs.

Introduction to Flare

Who should attend: Computational chemists.

Learn how simple structure-based design can be within small molecule discovery projects. The workshop will cover the calculation of the electrostatics of the protein active site, calculations of water stability and locations using 3D-RISM, energetics of ligand binding using WaterSwap, docking of ligands with Lead Finder and the minimization of protein-ligand complexes with the XED force field.

Introduction to Flare

Who should attend: Medicinal and synthetic chemists.

Chemists who are primarily interested in structure-based design will learn how Flare workflows and processes can be used to guide ligand design. Using the unique features of Flare you will design ligands that are electrostatically complementary to the protein active site. You will see how the innovative GUI makes the workflow simple.

Python in Flare

Who should attend: Computational chemists.

The Flare Python API brings scripting and customization to the Cresset suite. In this workshop you will learn how to use the Flare API to automate structure-based design tasks, implement new Flare functionality and make it accessible from the graphical user interface, carry out tasks with the RDKit and other third party tools and seamlessly import results back into Flare

Advanced Spark

Who should attend: Computational, medicinal and synthetic chemists.

Explore the new wizards in Spark to run advanced bioisostere replacement experiments. Learn how to set-up fragment linking, growing and macrocyclization experiments in an easy and scientifically robust manner by using the dedicated wizards and calculation methods.

Forge SAR

Who should attend: Computational, medicinal and synthetic chemists.

Learn how Activity Atlas and Activity Miner can help you to rapidly decipher the SAR of a series of molecules. See how efficient workflows are highlighted, and how to identify outliers with meaningful summaries of SAR that can inform molecule design.

Library design with Cresset nodes in KNIME

Who should attend: Computational chemists.

Using Cresset’s novel description of molecular similarity can really enhance library design. In this workshop you will learn to use Cresset’s Spark and Forge nodes for KNIME to create and analyze a virtual library design. You will use this informatics platform to study properties and diversity of the new library and discuss other approaches.

Abstracts

Stevan W Djuric, AbbVie Inc.

Drug Discovery has recently been described as a race by diMasi et al. Indeed, pressures to reduce cycle time and lower cost within the pharmaceutical industry are extreme. In this context, the presentation focuses on the use of enabling chemistry to accelerate drug discovery and reduce cycle time. Specifics covered will be the use of new flow chemistry technology including photochemistry and high temperature to access pharmacologically relevant molecules. Also covered will be the use of segmented flow chemistry for compound library production and the development of a best in class integrated synthesis-purification- bioassay platform which allows for the synthesis and testing of compound libraries in as little as two days.

Sneak Peek at Next Generation Collaborative 3D Design

Tim Cheeseright, Cresset

We are proud of our track record in innovation. From our first product Blaze to our most recent Flare we have consistently introduced new methods and new visualizations to our customer base. Central to our philosophy is to make computational methods accessible and intuitive, whether virtual screening 10M molecules or studying the SAR of 50.

We will present a sneak peek at our next innovation – a novel application for molecular design that puts the chemist and their collaborators at the centre of the process. Pivotal to this new application is the ability to design new molecules in 2D and visualize those designs in 3D in real time, with Cresset fields. Added to this is a collaboration layer such that colleagues can design together in a seamless way, whether they are in the same office or on different continents.

Real Time 3D Design in 2D!

Paolo Tosco, Cresset

How nice would it be to be able to draw a molecule in your favourite 2D sketcher, and see in real time how its 3D electrostatic potential looks, and maybe what interactions it makes in the target active site? We are sure you have thought of this many times, just as we did. This is why we decided to make it happen.

As you can imagine, there are a number of gotchas in this process. While you are growing and tweaking your ligand in the target site, it should not clash with the target itself; rather, it should automatically pick up the most favorable contacts available. If you are not so lucky to have a crystal structure available, you might still have some reference ligands to compare to in terms of field properties. Therefore, when you add an ortho or meta substituent on that aromatic ring, the algorithm should put it on the right side, in order to best fit that pocket, or mimic a certain electrostatic feature in the reference. The same should apply to the stereochemistry, where relevant. This talk will illustrate how we addressed these requirements.

Molecules in 5D: Experiences with Peptidic Macrocycles

Richard Lewis, Novartis

Peptidic macrocycles are good tools for investigating PPIs as they are natural mimetics for protein surfaces and have a smaller degree of conformational freedom. Processes such as the peptidream technology can be used to screen and select highly potent ligands. The challenge for CADD is to extract the information from such ligands, to help design small molecule analogues. The hierarchy of information goes from sequence to smiles to structure to conformer families to Boltzmann populations. The last two levels are particularly problematic, and I will describe progress in this area.

Flare V2: Raising the Bar in Structure-based Design

Mark Mackey, Cresset

When we launched Flare last year we promised that we were aiming to develop the best structure-based drug design application available. The release of Flare V2 brings us closer to that goal. In addition to major new scientific capabilities such as electrostatic complementarity calculations and ensemble docking, the new Python API will give you the opportunity to create custom workflows, new dialoqs, new tab menus, and add items to the existing menu structure. We’ve significantly improved the application on all levels, from data structures to surface visualization. In this talk we will walk you through the new Flare demonstrating just some of the many possibilities it opens up and take a look at some of the new features and enhanced capabilities that make Flare V2 a major new force in structure-based design.

Predicting Activity Using the Electrostatic ComplementarityTM of Protein-ligand Complexes

Matthias Bauer, Cresset

Electrostatic interactions between small molecules and their respective receptors are a key contributor to the free energy of binding. Assessing the electrostatic match between ligands and binding pockets provides therefore important insights into why ligands bind and what could be changed to improve binding.

The polarizable XED force-field is an excellent base for calculating electrostatic properties due to its description of anisotropic atomic charge distributions and relatively modest computational costs. By computing electrostatic potentials for both ligand and protein with XED, the electrostatic complementarity of complexes can be assessed via (1) inverse correlation of the respective local electrostatic potentials (Pearson or Spearman rho rank tests) or (2) calculating a normalized surface complementarity integral, yielding electrostatic complementarity scores. The latter approach also allows visualization of the local electrostatic matching on the van der Waals surface to identify electrostatic clashes and inform ligand design.

We present the theoretical background of our electrostatic complementarity descriptors along with several case studies showing the practical application of the scores to the prediction of activity and of the visualization to ligand design.

Ashraf Zarkan, Department of Genetics, University of Cambridge

The rise in antibiotic resistance and persistence is becoming increasingly important within the health and agricultural sectors, and finding solutions to these problems has a very high priority. Indole is an aromatic molecule with multiple and diverse signalling roles. Among the bacteria it regulates biofilm formation, virulence and response to a variety of stresses including the action of some antibiotics. Interfering with indole signalling could potentially provide a route for enhancing the activity of these antibiotics. However, indole signalling in bacteria remains poorly understood and a better understanding of its mechanism is of a great importance. Our group at the University of Cambridge is investigating the mechanism of indole action using E. coli as a model organism. One interesting recent discovery is a correlation between the effect of indole on the cytoplasmic pH of E. coli, and the ability of the bacterium to survive antibiotic stress. A recent study (Bartek et al, 2017) has proposed that antibiotics kill their target cells by increasing their cytoplasmic pH. Since indole acts to decrease the cytoplasmic pH, it seems likely that this explains at least some protection against antibiotics. Our collaboration with Cresset Discovery Services for the past year has been focused on identifying potential effective but non-toxic compounds that interfere with indole action, with an aim to develop a combination therapy for increasing the efficacy of some antibiotics.

Graeme Stevenson, Cancer Therapeutics CRC

Isoprenylcysteine carboxyl methyltransferase (ICMT) is a pivotal enzyme in the CaaX pathway, responsible for the post-translational modification of proteins which regulate cell growth, including the small GTPase superfamily, such as oncogenic kRAS.

Direct inhibition of oncogenic GTPases such as kRAS is impractical due to the affinity of GTP/GDP, hence indirect inhibition via prenyl transferase inhibition has to date been the only option. Despite major efforts prenyltransferase inhibitors have suffered from lack of efficacy, rendering the small GTPase system ‘undrugged’. We now wish to present data on the development of ICMT inhibitors as an alternative route for indirect inhibition of the small GTPase system.

Following an HTS campaign we identified low molecular weight inhibitors with a reasonable physicochemical profile based on a geminally disubstituted cyclohexane. Subsequent SAR development has delivered CTX-0294719 (ICMT: 211 nM) a substrate competitive ICMT inhibitor with a matched pharmacological and physicochemical profile allowing the observation of cell based consequences of ICMT inhibition. SAR development around CTX-0294719 has produced CTX-0295348 (ICMT: 0.3 nM), the first subnanomolar ICMT inhibitor.

CTX-0295348 is cell penetrant, inhibits ICMT activity and in doing so induces autophagy, inhibiting the proliferation of MDA-MB-231 cells. In addition we have identified that one outcome of ICMT inhibition is the mislocation of Lamin B1 an essential component of the nuclear laminae and a key factor in chromatin management. The conclusion of our research so far is that ICMT inhibition does offer a potential drug route for GTPase driven cancer and that Lamin B1 may be a potential new target for drug development.

New Science and Improved Workflows in Cresset Ligand-based Applications

Giovanna Tedesco, Cresset

What’s happened with ligand-based applications in the last year? I will describe the benefits of some of the new features and improvements which have made the great science in these applications better and easier to use. These include pharmacophore constraints and new similarity metrics in Forge, Torch, Spark and Blaze, the conformation explorer in Forge, an enhanced design workflow in Torch, and a brand new set of wizards in Spark to guide you through the most advanced experiments such as ligand growing, ligand joining, macrocyclization and water replacement.

Identifying Pharmaceutical Molecules with a Chemotyping Approach

Jun Xu, School of Pharmaceutical Sciences, Sun Yat-sen University

This talk introduces a de novo substructure generation algorithm (DSGA) that derives frequent substructures in order to avoid the subjectivity of empirical method, and avoid the meaningless substructures generated from algorithmic approaches by statistical analyses. DSGA derives frequent chemical substructures (FCS) from a large compound library. In a FCS, substructures are not inter-included. When the library is big enough to represent the chemical diversity, such as ZINC database (27 million medicinal compounds), the resulting FCS is termed as the FCS dictionary (FCSD) for drug-like compounds. For a focused compound library (FL), DSGA can derive a focused FCS (fFCS) from FL. fFCS can be used as structural descriptors for focus library SAR studies.

Six focused libraries against targets PDE4D, mTOR, HDAC1, DPP4, BACE and ALR2 were tested with DSGA approach. Using the fFCSs as structural descriptor sets, six virtual screening models were generated to predict ligands against the targets, the prediction accuracies are greater than 90%.

Three methods were proposed to assembly drug-like molecules from substructures: (1) using the laws in the nature, such as isoprene rule; (2) organic synthesis rules, such as retro-synthon rules proposed by E. J. Corey; (3) pharmaceutical rules derived from a focused compound library against a specific target. We use DSGA to figure out rules that are used to compose privileged scaffolds by assembling FCS.

It is still difficult to chemically make the compounds proposed by these assembling approaches. By combining DSGA method, bioisoterism method and Click Chemistry, we generated privileged substructures from Hsp90 inhibitor library, then find out available chemical fragments with bioisoterism rules. With SPR technology, we confirmed the fragments that interacted with Hsp90. Finally, we used click chemistry to assembly the substructures, and produced nanomolar selective Hsp90 inhibitors.

Kazuyoshi Ikeda, Keio University

Collaborative innovation in early drug discovery has made progress by utilizing computational approach. Keio University is constructing an informatics system for analyzing diversity of library compounds which are collected from a drug discovery screening consortium in Japan. Using the field-based approach, which is an improved method of the conventional pharmacophore model, we develop an automatic protocol to design a focused library for a specific drug target. The protocol can automatically generate a variety of the new bioisosteric molecules with druglike properties and patent-free structures from our own integrated database.

Recently, our colleagues conducted a compound screening contest where multiple research groups participated using different in-silico methods, and succeeded to find the hit compounds of pharmaceuticaly important drug targets such as Kinase and Epigenetic regulator from over 2 million commercially available compounds. We have performed a benchmark using the prediction and screening results and compared the different in-silico methods. In this presentation, I will introduce how to utilize the Cresset ligand-based tools for our library design study, and also discuss the ability of new structure-based design tool when applying for a large-scale compound library.

Antonia Mey, School of Chemistry, University of Edinburgh

Over the past 30 years computer-aided drug design has become a more and more prominent tool in drug discovery. In particular, using alchemical free energy calculations seems to provide the most promising avenue in terms of reliable scoring and ranking of potential drug molecules. However, setting up and running alchemical free energy calculations can still be complicated and challenging. In this talk I’ll give an introduction to SOMD, an application allowing to run alchemical free energy calculations and BioSimSpace a tool that will simplify running complex molecular dynamics workflows, such as alchemical free energy simulation protocols. At the same time I’ll discuss and illustrate common best practices for alchemical free energy simulations and their analysis as highlighted by the results of the D3R grand challenge 2016, a blinded challenge used for benchmarking computational prediction protocols of protein ligand binding affinities in comparison to experimental results.

Biographies

Matthias Bauer

Matthias graduated in pharmacy at the LMU Munich and obtained his PhD in pharmaceutical chemistry at the University of Tuebingen, followed by a postdoctoral fellowship in Sir Alan Fersht’s lab at the LMB in Cambridge.

His academic research focussed on the evaluation of virtual screening methods and development of new anticancer drugs targeting the p53 pathway via computational drug design and structural and biophysical characterization of small molecule ligands.

As a computational chemist at Cresset, Matthias works on internal research projects.

Tim Cheeseright

After a DPhil in Chemistry at the University of Oxford, Tim gained experience as a medicinal chemist and a molecular modeler at Peptide Therapeutics and Medivir. He joined Cresset immediately after its founding in 2002. He has been instrumental in developing the easy to use scientific software that characterises Cresset today.

As Director of Products Tim is responsible for Cresset software for computational chemists and medicinal chemists. His commitment to innovative, usable and accessible science is evident in every release.

Stevan W Djuric

Dr Stevan Djuric is head of the global AbbVie Medicinal Chemistry Leadership Team at Abbott and is also responsible for the Discovery Chemistry and Technology organization within their Discovery organization and chemistry outsourcing activities. The group’s current efforts are focused on new initiatives in the areas of high throughput synthesis and purification, hit to lead chemistry, chemical biology including target identification proteomics and new enabling technology identification and development.

He was named an AbbVie Distinguished Research Fellow in 2015.

During his tenure at Abbott Laboratories and AbbVie, Dr Djuric has been a Project Leader for groups in the Immunoscience, Metabolic Disease, and Antiinfective areas. Several of these programs have advanced compounds into clinical development and to the market including Abbott’s proprietary rapamycin analog, Zotarolimus, currently licensed to Medtronics for use on their vascular stents, marketed in the United States and Europe.

Dr Djuric has over 180 scientific publications, presentations and patents/applications pending. He has also given over 30 invited lectures at universities and national meetings. He is a member of several Editorial and Editorial Advisory Boards including the Journal of Medicinal Chemistry and ACS Medicinal Chemistry Letters and, in addition, holds an Adjunct Professorship in the Department of Medicinal Chemistry at the University of Kansas.

Kazuyoshi Ikeda

Kazuyoshi Ikeda obtained his PhD in Bioinformatics at Tokyo University of Pharmacy and Life Science in 2005. After a year as a Post Doc in Computational Biology Research Center, AIST Japan, he then worked as a principal researcher at PharmaDesign Inc from 2006 to 2009.

He moved to EMBL-EBI (European Bioinformatics Institute, Cambridge, UK), ChEMBL team for 3 years. During the time he was involved in developing drug discovery databases and applications. He is currently project associate professor in Keio University, Faculty of Pharmacy, and working for a drug discovery screening consortium project in Japan.

Richard Lewis

Richard started out as an organic chemist. He even spent a brief period as a (very) junior med chemist, making penicillins in Glaxo. However, at University, he did a course in pharmacology, and started to become more and more interested in why molecules did what they did. That led to a PhD in drug design with Philip Dean, who was also in the dept of Pharmacology. After a few years as an itinerant PostDoc learning about docking and proteins, Richard became 33% of Jon Mason’s group at RPR, leading it when Jon moved to the US, moving to Lilly to lead the European CADD team, before joining Novartis in 2004.

Richard has worked on kinases, proteases, transporters, ion channels, GPCRs and dabbled in nuclear hormones. Once he even had the misfortune to be given a PPI to look at where the association constant for the natural partners was picomolar. He has also worked in diversity set selection, combinatorial library design, written some of the first tools to handle problems in these areas. More recently, Richard has been working on tool kits for medicinal chemists, in particular around ADME. Richard’s current interests are using big data and decision making. He has published over 60 papers and patents.

Mark Mackey

Mark was one of the founders of Cresset when the company was formed in 2002. He became CSO in 2013 and heads up our scientific team.

Mark has made fundamental contributions to our underlying scientific approach and to the development of the software. He works hard to extend the scientific base of the company in a way that is consistent with our reputation of rigorous scientific excellence. His team’s current research includes new ways of applying the XED force fields to proteins and improving the handling of water molecules.

Mark’s previous experience includes roles at Napp Pharmaceuticals and Merck, Sharpe and Dohme. His PhD is in Chemistry from the University of Cambridge and he is a Fellow of the Royal Society of Chemistry.

Antonia Mey

Antonia Mey is a postdoctoral research associate in the School of Chemistry at the University of Edinburgh. She obtained a BSc from Keele University in Physics and Chemistry and a PhD in Physics from the University of Nottingham. Before joining Dr Julien Michel’s group at the University of Edinburgh in 2015 she was part of the Computational Molecular Biology group at the Freie Universität in Berlin in the Department of Mathematics and Computer Science. Her main research interests lie in the field of molecular recognition and in particular algorithmic development for improving the reliability and accuracy of free energy calculations.

Rob Scoffin

Rob is an expert in the fields of molecular modeling and cheminformatics. His previous roles include CEO of Amedis and VP, Europe at CambridgeSoft. He also heads up Re-Pharm, an early stage discovery company which uses Cresset software to assess compounds for repurposing. His DPhil is in Chemistry from the University of Oxford.

Rob is passionate about applying computational methods to help meet medical challenges. He believes drug discovery and design can be streamlined and improved through the use of computational methods, resulting in better drugs being brought to market sooner. Rob is a Fellow of the Royal Society of Chemistry.

Graeme Stevenson

Graeme graduated from the University of Edinburgh with a chemistry degree in 1987. He then moved to Merck and Co, Terlings Park, Harlow, UK where he worked in medicinal chemistry, Molecular Discovery Research and Psy CEDD. In 2008 Graeme moved to Australia where he took the role of principal research Fellow at Griffith University Australia as CTx group leader. Since 2014 Graeme has been Director of Computational Chemistry at CTx.

Giovanna Tedesco

Dr Giovanna Tedesco joined Glaxo in 1990. As senior computational chemist she supported a variety of drug discovery programs in the antibacterials and CNS areas, and led target-to-lead CNS programs. When Aptuit took over the GSK site in Verona, Giovanna moved to client services where she worked as a senior proposal driver.

Giovanna joined Cresset in December 2014. As product manager she has responsibility for delivering software for computational chemists.

Paolo Tosco

Paolo completed his PhD in Drug Science in 2002 at the University of Turin (Italy), and in 2004 he was appointed Assistant Professor in Medicinal Chemistry. Starting from 2005 he gradually moved from synthetic chemistry to computational chemistry, which is currently the focus of his research interests. From 2008 to 2013 he released a number of open-source packages dedicated to molecular alignment and 3D-QSAR, and established successful collaborations with both academic (University of Geneva, University of Copenhagen) and industrial research groups (COSMOlogic, Novartis Institutes for Biomedical Research). In 2012 he was the winner of the Teach-Discover-Treat challenge, an initiative promoted by the COMP division of ACS to foster the development of drug discovery computational workflows for neglected diseases. In 2014 he joined Cresset as Computational Chemistry Developer.

Jun Xu

Jun Xu completed his PhD from University of Science and Technology of China, and postdoctoral studies from Australian National University and McGill University. He is the founding director of Research Center for Drug Discovery(RCDD), which consisits of Bio/Chemo-informatics lab, Drug Design lab, Phyto/Medicinal Chemistry lab, Structure biology lab, and Drug Screening lab. He has published more than a hundred papers in peer-reviewed and reputed journals. He has been serving as an editorial board member of a number of reputed international journals. He is also the adjunct Professor of University of Pittsberg (Pittsberg, USA) and RMIT Univeristy (Melbourne, Australia).

Prof. Xu’s research involves in chemistry, pharmacy and informatics. Since the last century, he has been developing algorithms for chemoinformatics / bioinformatics and pharmaceutical innovations, such as GMA (substructure/superstructure search, 1980s) CPA (fuzzy graph algorithm for protein structure determination from multi-dimensional NMR, 1990s), SCA (clustering large compound libraries, 2000s) and DLI algorithm (drug-like index, 2000s); WEGA (3D molecular superimposing, 2010s) DSGA (de novo frequent substructures recognition, 2010s). With these methods, his team discovered many drug leads against inflammation, virus, cancer and metabolic diseases. The lead compounds against nasopharyngeal carcinoma have entered the pre-clinic studies. Prof. Xu has published about hundred papers in international peer-reviewed journals. He is the inventor of more than 20 patents.

Ashraf Zarkan

Ashraf Zarkan is a Post-Doctoral researcher in the Summers lab, Department of Genetics, University of Cambridge. He identifies himself as a microbiologist with a pharmaceutical background and a passion to tackle the increasing problem with antibiotic resistance. He obtained his PhD in Biochemistry from the University of Cambridge (2012 – 2016). He holds an MSc in Medical and Molecular Microbiology from the University of Manchester (2010 – 2011) and a BSc in Pharmacy and Pharmaceutical Chemistry from the University of Damascus, Syria (2002 – 2007). He has a diverse work experience, including academia (Research, supervision and lab demonstration: 2013 – now) and pharmaceutical industry (Pharmacist and Medical representative: 2007 – 2009). His current research is focused on investigating the mechanism of indole signalling in E. coli as a potential route for enhancing the activity of antibiotics and tackling the issue of antibiotic resistance.